16, 16-difluoroestratrienes and intermediates relating thereto



States atent 3,648,62 Eatented Aug. 7, 1952 his 3,043,60216,16-DIFLUOROESTRATRIENES AND INTER- MEDIATES RELATING THERETO Cecil H.Robinson, Cedar Grove, N.J., assignor to Schering Corporation,Bloomfield, Ni, a corporation of New Jersey No Drawing. Filed Feb. 5,1962, Ser. No. 171,275 1 Claim. (Cl. 260-3971) This invention relates toa new group of therapeutically active steroids. More specifically, thisinvention relates to novel 16,16-difluoroestratrienes. In particular, myin vention encompasses 16,16-difluoro derivatives of estrone, estradiol,17a-alkylestradiol and '17a-ethinylestradiol. Also included within thescope of my invention are the esters and 3-lower alkyl ethers of theaforementioned 16, 16-difluoroestratrienes as well as novelintermediates used in the preparation thereof.

My novel 16,16-difluoroestratrienes have the following general formula:

wherein Z is a member of the group consisting of O, (H, ,BOR), (oc-lOWCIalkyl, 180R), (or-IOWSI alkenyl, 30R) and (at-lower alkynyl, 50R)wherein R is a member of the group consisting of H and an acyl radicalof an acid of the group consisting of carboxylic acids containing up toeight carbon atoms, sulfate and phosphate, and R is a member of thegroup consisting of hydrogen, lower alkyl and an acyl radical of an acidof the group consisting of carboxylic acids containing up to eightcarbon atoms, sulfate and phosphate.

By the terms lower alkyl, lower alkenyl and lower alkynyl arecontemplated hydrocarbon radicals having preferably up to four carbonatoms, the alkynyl radicals having the triple bond stemming from thecarbon adjacent to the steroid nucleus. Included are alkyl radicals suchas methyl, ethyl, isopropyl, n-propyl, n-butyl and the like; alkenylradicals such as ethenyl (vinyl), propenyl (allyl), and ot-butenyl; andalkynyl radicals such as ethynyl, 1-propynyl and 1-butynyl.

Illustrative of the 3 and/ or 17 acyloxy radicals contemplated are loweralkanoates such as acetate, propionate, butyrate, valerate, caproate andt-butylacetate; aryl esters such as benzoate and toluate; esters fromdibasic organic acids such as succinate, phthallate and sulfobenzoates;and those from polybasic inorganic acids such as sulfate, phosphate andthe like. Also included in the term acyloxy radical are alkali metalsalts of dibasic organic acid esters and of polybasic inorganic acidesters, for example, 3-methoxy-16,16-difluoroestradiol 17-sodiumsuccinate and 16,16-difiuoroestrone 3-disodium phosphate, respectively.

My invention therefore relates to compounds such as 16,16difluoroestrone (16,16difluoro-1,3,5(l)-estratriene-3-ol-17-one),16,16-difluoroestradiol (16,16-difiuoro- 1,3,5() estratriene3,17,8-di0l), 16,16-difluoro-17et methylestradiol 16,16 difluoro17a-methyl-1,3,5(10)- estratriene-3 ,17B-diol)16,16-difiu0ro-17a-ethinylestradi0l (16,16difiuoro-17a-ethinyl-1,3,5(10)-estratriene-3,17,8- diol) and to 3-loweralkyl ethers such as 3-methoxyand 3 ethoxy16,16-difluoro-1,3,5(10)-estr-atriene-17-one, 3- methoxy 16,16difiuoro-17u-methyl-1,3,5(10)-estratriene 17/3 ol,3-methoXy-16,16-difluoro-17u-ethinyl-1,3,5-

. 16-difluoroestratriene, e.g.,

(10)-estratriene-17p-ol, and 3-methoxy-16,16-difluor0-1,3,5,(10)-estratriene-17/3-ol. Also included are mono-esters such as16,16-difluoroestrone 3-acetate (16,16-difluoro1,3,5(10)-estratriene-3-ol-17-one Z-acetate), 16,16-difluoroestrone3-benzoate, 16,16-difluoro-17tx-m.ethyl-1,3,5(10)- estratriene3,175-diol 17-acetate, 16,16-diflu0ro-1,3,5-(1'0)-estratriene-3,17;8-diol 3-acetate, 16,16-difill0I'O-17uethinyl1,3,5(10) estratriene-3,17fi-diol B-benzoate, 3- methoxy16,16-difluoro-1,3,5 (10)-estratriene-17B-ol 17- hemisuccinate,3-methoxy-16,16-difluoro-1,3,5( 10 -estratriene-17fi-ol 17-phosphate;and diesters such as 16,16- difiuoro-1,3,5 10) -estratriene-3,17/3-dioldibenzoate, 16, 16-ditluoro-1,3,S(10)-estratriene-3,17 8 liol 3-acetate17- benzoate, 16,16-difluoro-17a-ethinyl-1,3,5(10)-estratriene-3,17B-diol 3 'oenzoate 17-acetate and 16,16-difluoro-1,3,5- (10)-estratriene-3,17(3-diol diacetate.

My novel compounds are therapeutically active as described herein. Ingeneral, the 3-l0wer alkyl ethers of the generic formula are moretherapeutically valuable than are the 16,16-difiuoroestratrienes havinga free hydroxyl or an acyloxy group at the 3-carbon. In particular, the3-methyl ethers are the preferred species and specifically,3-methoXy-16,16-difluoro-1,3,5-(10)-estratriene- 17 one, 3methoxy-l6,16-diflu0ro-1,3,5(10)-estratriene- 175 01,3-rnethoxy-l6,16-difiuoro-l7ot-methy1-1,3,5 10)- estratriene 17,6 01 and3-methoxy-16,16-difluoro-17aethinyl-1,3,5 10) -estratriene-17[3-ol.

My novel compounds are conveniently prepared from a precursor containingno other substituent in the D-ring except a 17-keto function (forexample, estrone benzoate or a lower alkyl ether of estrone such as3-methoxy-1,3, 5 (10)-estratriene l7-one) by utilizing the novel processdescribed in copending application of Robinson, Serial No. 7,107, filedFebruary 8, 1960. According to this process an estratriene having aketone function at C17, for example, 3-methoxyestrone is converted tothe intermediary 16-hydroxymethylene or 16-ethoxalyl derivative bymethods well known in the art. I prefer to formulate the activated C16position by reacting S-methoxyestrone, for example, with ethyl formateand sodium methoxide or sodium hydride utilizing as solvent, benzene ortetrahydrofuran or mixtures thereof. The 16-formyl derivative therebyobtained, i.e.,3-methoxy-16-hydroxymethylene-1,3,5(10)-estratriene-17-one exists in twotautomeric forms, namely formyl and hydroxymethylene. Alternatively, the16-ethoxaly1 derivatives of estrone, estrone benzoate orB-methoxyestrone are prepared according to procedures similar to thosefor preparing the 16-hydroxymethylene denivatives by using ethyl oxalateas reagent instead of ethyl formate, yielding derivatives which alsoexist in two tautomeric forms (keto and enol), the keto derivativesbeing 16-ethoxalylestrone, 16-ethoxalylestrone benzoate and3-methoxy-16-ethoxaly1estrone, respectively, and the respective enolforms being 16-(1'-hydroxy-1'- carbe'thoxy)methyleneestrone, 16-(1'hydroxy-1'-carbethoxy)methyleneestrone 3-benzoa te, and 3methoxy16-(1'-hydroxy-1-canbethoxy)methyleneestrone.

By reacting an intermediary 16-hydroxymethyleneestratriene(16'formylestratriene) or 16-(1'-hydroxy-1-carbethoxy)methyleneestratriene 16-ethoxalylestratriene) for example, 3-methoxy-16hydroxymethylene-1,3,5(10)- estratriene-17-one, with perchloryl fluoridein the presence of alkoxide, preferably potassium t-butoxide in tbutanolsolvent, there is obtained the corresponding 16,3-methoxy-16,16-difiuoro-1,3, 5(10)-estratriene-17-one, a novel compoundof my invention.

The novel 3-methoxy-16,16-difluoro-l,3,5(10)-estratriene-17-one,prepared as described above, may be transformed to the 17C6-lOWeI'alkynyl-17B-hydroxy or clower alkyl-17/8-hydroxy analogs by knownmethods. For example, 3-rnethoxy-16,16-difluoro-1,3,5 10) -estratriene-17-one is readily transformed to3-methoxy-16,16-difiuoro-17a-methyl-l,3,5( l) estratriene-171301 by thewell known Grignard reagent utilizing methyl magnesium iodide, or istransformed to the corresponding 17a-ethinyl compound by means of sodiumor potassium acetylide. The 17-keto compound, e.g.3-methoxy-16,16-difluoro- 1,3,5 ()-estratriene-17-one is reduced to thel7fi-hydroxy analog (3-methoxy-16,16-dif1uoro-1,3,5 10) estratriene-175-01) by hydrogenation with lithium aluminum hydride, Sodiumborohydride, platinum-hydrogen and the like.

By substituting suitable reagents in the aforementioned reactions suchas ethyl magnesium bromide instead of methyl magnesium iodide in theGrignard reaction on 3-methoxy-l6,16-dif1uoro-1,3,5(10)-estratriene-l7-one there are obtainedhigher homologs at C17 for example, 3- methoxy-16,16-difluoro 17aethyl-1,3,5 (10)-estratriene- 17fl-ol. Similarly, to prepare C17homologs of 3-methoxy-l6,16-difluoro 17a ethinyl 1,3,5(l0) estratriene-17,B-o1 for example, it is preferred to substitute sodium or potassiummethyl acetylide for sodium acetylide in the alkynylation reaction toobtain the corresponding 17a- (l-propynyl) analog. When sodiumethylacetylide is used in the aforementioned reaction there is obtainedthe corresponding 17a-butynyl compound, i.e. 3-methoxy-16,l6-difluoro-17a-(1-butynyl) 1,3,5(10) estratriene- 175-01.Alternatively, it is possible to obtain higher 170:- alkynyl homologs ofmy 17a-ethinyl compounds by alkylating the active hydrogen on theethinyl moiety by means of lithium and methyl or ethyl iodide, forexample, to obtain the corresponding l7oc-(l'-propynyl) or 170;-(l-butynyl) compound.

The 16,16-difluoro-17u-alkenylestratrienes of the general formula areconveniently prepared from the correspondingl6,16-difluoro-17a-alkynylestratrienes by reduction with hydrogen in thepresence of pallidized strontium carbonate catalyst. For example,3-methoxy-16,l6-difluoro-17wethynyl 1,3,5 (10) estratriene-l7fl-ol and3- methoxy 16,16 difiuoro-17ot-(1-propynyl)-l,3,5(10)- estratriene-17501upon reduction yields 3-methoxyl6,16- difill01'O-17oc-ViI1Y1- 1,3,5(l0)-estratriene-17,8-ol and 3- methoxy 16,16difluoro-l7oc-(l-propynyl)-1,3,5(10)- estratriene-17B-ol, respectively.

When preparing the novel 16,16-difiuoroestratnienes having a freehydroxy group at the 3-carbon it is preferred to introduce the16,16-difiuoro moiety into a 3- alkyloxy derivative of estrone and thenhydrolyze the alkoxy group to hydroxy by known techniques such as thatutilizing hydroiodic acid in the presence of acetic acid, or hydroiodicacid together with an inert solvent such as dioxane. Alternatively,estrone 3-benzoate is converted to 16,16-difiuoroestrone S-benzoatewhich, in turn, is hydrolyzed by means of methanolic potassium hydroxideto 16,16-difluoroestrone.

My novel 3,17-dihydroxy-16,l6-difluoroestratrienes are obtained from16,16-dif1uoroestrone by procedures analogous to those described abovefor the 3-methoxy compounds of my invention. Alternatively, the3,17-diols of the general formula may be obtained from the corresponding3-methoxy derivative by hydrolyzing the ether group at the 3-carbon asdescribed heretofore. For example,16,16-difluoro-17a-methyl-1,3,5(10)-estratriene- 3,17p?-diol is preparedfrom 16,16-difluoroestrone by utilizing the Grignard reagent methylmagnesium iodide, or, alternatively is prepared from3-methoxy-l6,16-difluoro- 17amethyl-'1,3,5 (10)-estratriene 17B 01 byhydrolysis with hydroiodic acid in the presence of acetic acid.

The 3-alkyloxy-16,16-dif1uoroestratrienes of the general formulapossessing an ester group at C17 are conveniently prepared by knowntechniques from the corresponding 3 alkyloxy 17,8 hydroxy 16,16difluoroestratriene by esterification with pyridine and an acidanhydride. For example,3-methoxy-16,16-difluoro-17amethyl-1,3,5(10)-estratriene-17fi-ol whenheated with acetic anhydride in pyridine yields the 17-acetate, i.e. 3methoxy 16,16 difluoro 17a methyl 1,3,5'(10)- estratriene-17fi-ol17-acetate. By substituting other lower alkanoic acid anhydrides such aspropionic anhydride or caproic anhydride; or a dicarboxylic acidanhydride such as succinic or phthalic anhydride; or acid halides ofaryl carboxylic acids such as benzoyl chloride, the corresponding17-ester is obtained, i.e. the 17-propionate, 17-caproate, 17-succinate,l7-phthalate and 17-benzoate respectively of3-methoxy-16,16-difluoro-17umethyl-1,3,5 l0) estratriene-17501.

The inorganic acid esters of my novel 16,16-difluoroestratrienes arealso prepared in pyridine utilizing known techniques. For example,3-methoxy-16,16-difluoroestradiol in pyridine upon reaction withphosphorous oxychloride yields 3-rnethoxy-16,16-difiuoroestradio117-phosphate. An alkali metal salt of the foregoing ester such as thedisodium salt is then conveniently prepared by reaction of the phosphateester with sodium hydroxide to give 3-methoxy-l6,16-difluoroestradio117-disodium phosphate.

When preparing 3,17-diesters of the general formula, the corresponding3,17-dio1 is preferably reacted in pyridine with at least two moles ofan acid anhydride or two moles of an acid chloride per mole of steroid.Usually an excess of acid anhydride or acid halide is used, and it isoften desirable to apply heat to hasten the esterification process. Forexample, l6,16-difiuoro-1,3,5(l0)- estratriene-3,17 8-diol dibenzoate isobtained from 16,16- difiuoroestradiol by reaction with a two molarexcess of benzoyl chloride.

Those compounds of my invention possessing an ester group at the3-position and a secondary hydroxyl at the 17-.position, for example,estradiol 3-acetate are conveniently prepared by known techniques fromthe corresponding 3-acyloxy-l7-one, i.e. estrone 3-acetate by reductionwith hydrogen utilizing platinum oxide as catalyst. The

3-acyloxy-16,16-difiuoroestratriene possessing a tertiary hydroxyl atC-17 are conveniently prepared from the corresponding 3,17dihydroxy-l6,16-difluoroestratrienes by selective esterification at 0-3with pyridine and a lower alkanoyl anhydride, or with pyridine and anacid chloride of an aryl carboxylic acid such as benzoyl chloride. Forexample, 16,16-difluoro-l7a-methyl-l,3,5(10)- estratriene-3,17B-diolreacted with approximately a molar equivalent of acetic anhydride inpyridine yields the 3-monoacetate, i.e.16,16-difluoro-17a-methyl-1,3,5(10)- estratriene-3,17fl-diol 3-acetate.Similarly, reaction with approximately a molar equivalent of benzoylchloride in pyridine yields the 3-monobenzoate, i.e. 16,16-difiuoro-.17oc-methyl-1,3,5 l0) -estratriene-3,17/3-diol 3-benzoate.

By varying reaction conditions and utilizing a combination of knowntechniques there are obtained compounds of the general formula havingdissimilar ester groups at C3 and C17. For example, reaction of a3-acyl0xy-16,16-difluoro-17a-hydroxyestratriene with an acid anhydrideor acid halide having an acid radical other than that at the 3-position,such as the reaction of 16,16- difluoro 17a methyl 1,3,5(10) estratriene3,17,6- diol 3-benzoate with acetic anhydride in pyridine at elevatedtemperatures, will yield the mixed 3,17-diester, 16,16 difluoro 17ccmethyl l,3,5(10) estratriene- 3,17 3-diol 3-benzoate l7-acetate.

A 3,17-diol of the general formula possessing an ester group at 17 suchas 16,16-difiuoro-17a-methyl-1,3,5(l0)- estratriene-3,17fl-diol and17-acetate and 16,16-difluoroestradiol 17-acetate is convenientlyprepared by known techniques from the corresponding diester16,16-difluorol7u-ethyl-1,3,5(10)-estratriene-3,17fi-diol diacetate and16,16-difiuoroestradiol diacetate by partial hydrolysis such as with 5'%potassium hydroxide or 1% potassium carbonate in methanol, respectively.

The novel 16,16-difluoroestratrienes of the general formula, andparticularly the 3-lower alkyl others, are therapeut-ically valuable inthat they exhibit low estrogenic activity in conjunction with a stronglipid-shifting ellect (i.e. in addition to lowering serum cholesterolthey cause a reduction in serum phospholipids as well). This combination of properties (i.e. low estrogenic-high lipidshifting), rendersmy novel compounds valuable in the treatment and prevention ofconditions such as arteriosclerosis which are caused by abnormalcholesterol metabolism and deposition. It is known that est-ratrienessuch as estrone and estradiol also possess this lipid effect. However,these compounds are also potent estrogens, and the strong estrogenicside effects of these compounds renders them impractical for the longterm therapy necessary when treating degenerate diseases such asarteriosclerosis. My novel 16,16-difiuoroestratrienes on the other hand,surprisingly possess a minimum of estrogenic activity while retaining astrong lipid-shifting effect. This is clearly demonstrated by the ratioof the lipid-shifting effect to the estrogenic effect, which in my novelcompounds is dramatically increased over the corresponding ratioscharacteristic of the natural estrogenic hormones. For example,16,16-difiuoroestrone 3-methyl ether exhibits approximately the samelipid-shifting effect as estradiol in the rat while exhibiting merelyabout 0.05% of the estrogenic activity of estradiol as measured by themouse uterine assay. Thus, the ratio of lipid-shifting activity toestrogenic activity as compared to the same ratio for estradiol is about2,000 to 1.

In addition to the foregoing, my fluorinated estratrienes possess theadded advantage of being long acting. For example, it has been observedthat 3-methoxy-16, l6-difluoroestrone causes a lowering of serumcholesterol in the rat for longer periods of time than does estradiol.By exhibiting extended pharmacological activity in conjunction with aminimum of undesirable side effects my compounds are rendered valuabletherapeutic agents.

In addition to being therapeutically valuable per se, my novel16,16-difluoroestratrienes are useful as intermediates in thepreparation of other pharmacologically active steroids such as the16,16-difluoro-l9-nor-4-androstenes described in copending application,Serial No. 7,107, filed February 8, 1960. For example, 3-methoxy16,16-difluoro-1,3,5 (10)-estratriene-17[1-ol upon reduction with lithium inammonia according to known techniques yields 3 methoxy 16,16 difluoro2,5(10) estradiene- 17B-ol which upon subsequent treatment with a strongacid such as hydrochloric is converted to16,16-difluorol9-nor-4-androstene-17B-ol-3-one. Alternatively, when 3methoxy 16,16 difluoro 2,5(10) estradiene- 175-01 is treated with a weakacid such as oxalic acid there is obtained16,16-difluoro-(10)-androstene-17[3-ol- 3-one which is convertible uponhydrochloric acid treatment to the therapeutically active 4-dehydroisomer, 16,16 difluoro -19 nor 4 androstene 17p ol 3- one. Conversion ofthe 17B-hydroxyl group to the 17- keto function is effected by chromicacid oxidation.

The 16,16 difluoro 17 keto 19 nor 4 androstene-3-one thus obtained whensubjected to reactions similar to those described hereinabove for the16,16-difluoro- 17-ketoestratrienes of this invention, is convertible tothe corresponding l7a-methyl-17fi-hydroxy-, and the 17stethinyl 17Bhydroxy 16,16 difluoro 19 nor 4- androstene-3-one.

The following examples are shown by way of illustration only and are notto be construed as limiting the scope thereof, the scope of my inventionbeing defined by the appended claims.

The present application is a continuation-in-part of my copendingapplication, Serial No. 7,124, filed February 8, 1960.

EXAMPLE 1 A. 3 methoxy 16 hydroxymerhylene 1,3,5()-estratriene-17-0ne.--To a stirred solution of g. of3-methoxy-1,3,5(10)-estratriene-17-one in 600 ml. of tetrahydrofuranunder an atmosphere of nitrogen, there is first added 25 g. of sodiummethoxide and then, over a minute period, 200 ml. of ethyl formate. There- 6 action mixture is stirred under nitrogen for 18 hours at roomtemperature, then is poured into water. The resulting solution isacidified with 6 N aqueous hydrochloric acid. A solid precipitates whichis filtered off and dried in vacuo to give substantially 3-metnoxy-16-hydroxymethylene-1,3,5 l0) -estratriene-17-one,

x3 52 268 mu (6 10,500)

which is used without further purification in the following procedure.

B. 3 methoxy 16,16 difluoro 1,3,5(10) eslratriene-17-0ne.-To 4.2 g. of3-methoxy-16-hydroxymethylcue-1,3,5(10)-estratriene-17-one dissolved in450 ml. of t-butanol, there is added ml. of a molar solution ofpotassium t-butoxide in t-butanol. Perchloryl fluoride gas is thenbubbled through this stirred solution under nitrogen for minutes at roomtemperature. The reaction mixture is diluted with 2 l. of water andextracted with methylene chloride. The extracts are combined, washedwith water, dried over magnesium sulfate and evaporated in vacuo. Theresi'iltant residue is chromatographed on Florisil and eluted withhexane-ether mixtures. The hexane-ether eluates ranging in concentrationfrom 7:3 to 1:1 are combined and crystallized from ether-hexane to give3-methoxy-l6,16-difluoro-1,3, 5(10)-estratriene-17-one, MP. 126-l28 C,[M +167,

EXAMPLE 2 3-Meth0xy-J6,16-Difluor0-1,3,5 (10 -Eszratriene-1 75-01 300mg. of sodium borohydride is added to a solution of 170 mg. of3-methoxy-16,16-difluoro-1,3,5(10)- estratriene-17-one (the compound ofExample 1) in 14 ml. of isopropanol. The reaction mixture is refluxedfor one hour then cooled and diluted with water. The resultant solid isfiltered, washed with water, dried and crystallized from aqueousmethanol to give 3-methoxy- 16,16 difiuoro 1,3, 5(10) estratriene 01,MP. 123l27 C., [a1 +71.

EXAMPLE 3 To a stirred solution of 500 mg. of 3methoxy-16,16-difluoro-1,3,5(10)-estratriene-17-one in 7 ml. of dimethylsulfoxide,there is added sodium acetylide (obtained from 4 ml. of a 17% suspensionof sodium acetylide in xylene by centrifuging and removing thesupernatant liquid) in 5 ml. of dimethylsulfoxide. The reaction mixtureis stirred at room temperature for 45 minutes, then diluted with ice andwater. A solid separates which is filtered, washed with water, dried andcrystallized from acetone-hexane to give3-1'nethOXY-l6,l6-ClifluOrO-17oaethinyl-1,3,5(l0)-estratriene-l7B-ol,MP. 140l42 C. [(111 +20 In a similar manner by substituting sodiummethyl acetylide for sodium acetylide in the above procedure, there isobtained 3-methoxy-16,l6-difiuoro-l7u-uropynyl- 1,3 ,510)-estratriene-17fi-ol.

EXAMPLE 4 3-Methoxy-16,16-Difluor0-1 7a-Meth "I-1,3,5(10)- Estratriene-J75-01 To a stirred solution of methyl magnesium iodide (derived from 1.5g. of magnesium and 4 ml. of methyl iodide) in 100 ml. of ether under anatmosphere of nitrogen, there is added 500 mg. of3-methoxy-16,16-difiu0ro- 1,3,5(10)-estratriene-17-one (the compound ofExample 1) in 25 ml. of tetrahydrofuran. An additional 75 ml. oftetrahydrofuran is added and the ether is distilled out of the reactionmixture. The remaining mixture is then refluxed for one hour, thencooled and added cautiously to a mixture of ice and water. The aqueousmixture is extracted with methylene chloride. The extracts are combined,Washed With Water, dried over. magnesium sulfate and evaporated in vacuoto a residue which is chromatographed over Florisil. Benzene-ethereluates ranging in concentration from 1:1 to 1:9 are combined andevaporated to a residue which is crystallized from ethyl acetatemethanolto give 3-methoxy-16,16-difluoro-17u-methyl-1,3,5(10)-estratriene-17/3-ol, MP. 137142 C.

In a similar manner by substituting other alkyl Grignard reagents suchas ethyl magnesium iodide and Ilpropyl magnesium bromide for methylmagnesium iodide in the above procedure, there is obtained 3-methoxy-16,16 difluoro 17a ethyl 1,3,5(10) estratriene 17,6-01 and3-methoxy-16,16-difluoro-17ot-n-propyl-1,3,5 (10) estratriene-17601,respectively.

EXAMPLE 5 3 -M ethOxy-J 6 ,1 6-D ifluoro-I ,3 ,5 (I -Estratriene- 175-0117-Acetate To one gram of 3-methoxy-16,16-difluoro-1,3,5(10)-estratriene-17,801 (the compound of Example 2) in 10 ml. of pyridine isadded 2 m1. of acetic anhydride. The solution is left overnight at roomtemperature. Water is added and the aqueous mixture extracted withether. The ether extracts are combined, washed with 2 N hydrochloricacid, then water, dried over sodium sulfate, filtered and distilled invacuo to give a residue substantially of 3- methoxy 16,16 difluoro1,3,5(10) estratriene 1713- 01 17-acetate.

Similarly, by substituting other lower alkanoic acid anhydrides such aspropionic, valeric or caproic for acetic anhydride in the aboveprocedure, there is obtained the corresponding 17-propionate,17-valerate and 17-caproate respectively of3-methoxy-16,16-difluoro-1,3,5(10)-estratriene-lZB-ol.

EXAMPLE 6 The 17-Acetate Ester of 3-Methoxy-16,16-Diflu0r0-17on-Ethinyl-1,3,5(10)-Estratriene-17fl-ol and 3-Meth0xy- 16,16 Difluoro 17aMethyl-1,3,5(10)-Estratriene- T 0 one gram of3-methoxy-16,16-difluoro-17a-ethinyl- 1,3,5 (10)-estratriene-17/3-o1(the compound of Example 3) in 10 ml. of pyridine is added 2 ml. ofacetic anhydride. The reaction mixture is heated on the steam bath for48 hours, then cooled. Water is added and the aqueous mixture isextracted with ether. The extracts are combined, washed with 2 Nhydrochloric acid, then Water, dried over sodium sulfate and distilledin vacuo to give a residue substantially of 3-methoxy-16,16-difluoro-17a-ethinyl-l,3,5(10)-estratriene-l7fi-ol 17 acetate.

In the manner described above3-methoxy-16,16-difiuor0-17ot-methyl-1,3,5(10)-estratriene-17B-ol (thecompound of Example 4) is reacted with acetic anhydride in pyridine togive 3-methoxy-16,16-difluoro-17ot-methyl- 1,3,5(10)-estratriene-17fi-ol17 -acetate.

Similarly by substituting other lower alkanoic acid anhydrides such aspropionic, valeric or caproic for acetic anhydride in the aboveprocedures, there is obtained the corresponding 17-propionate,17-valerate and 17-caproate respectively of3-methoxy-16,16-difluoro-17a-ethinyl-1,3,5 (10)-estratriene-17fl-ol andof 3-methoxy-16,16-difluoro- 17ix-methyl-1,3,5(10)-estratriene-17/3-ol.

EXAMPLE 7 16,16-Diflu0r0-1 ,3,5 (10) -Estratriene-3-Ol-17-One A solutionof 1 g. of 3-methoxy-16,16-difluoro-1,3, 5(10)-estratriene-17-one in ml.of glacial acetic acid and 2.5 ml. of constant boiling aqueoushydroiodic acid (density 1.5) is refluxed for two minutes. The solutionis cooled, poured into 10% aqueous sodium bisulfite solution, then thereis added 10% aqueous sodium hydroxide solution. The reaction mixture isfiltered, the filtrate brought to neutrality with acetic acid, thenextracted with ether. The ether extracts are combined, Washed withwater, dried over sodium sulfate and evaporated in vacuo 8 to a residuesubstantially of 16,16-difiuoro-1,3,5(l0)- estratriene-3-0l-l7-one.

Similarly, 3 methoxy-16,l6-difiuoro-1,3,5(10)-estratriene-l7fl-ol (thecompound of Example 2) is hydrolyzed with aqueous hydroi-odic acidaccording to the above procedure to give16,16-difluoro-1,3,5(10)-estratriene-3,17B- diol.

EXAMPLE 8 16,16-Diflu0r0-1 7ot-Methyl-1,3,5 (10)-Estratriene- 3,17fl-Di0l 16,16 difiuoro 1,3,5( l0)-estratriene-3 ol-17-one (the compoundof Example 7) is reacted with methyl magnesium iodide in the manner ofExample 4. The resultant r product is isolated and purified as describedto give 16,16-

difluoro-l7a-methyl-1,3,5(10)-estratriene3,17/3-diol.

EXAMPLE 9 1 6 ,1 d-Difluoro-I 7 a-E th iny l-] ,3 ,5 (1 0 -Estratriene-3,1 7,6-Di0l 16,16 difluoro 1,3,5 10)-estratriene-3-ol-l7-one (thecompound of Example 7) is reacted with sodium acetylide indimethylsulfoxide according to the procedure of Example 3. The resultantproduct is isolated and purified in the manner described to give16,16-difiuoro-17a-ethinyl- 1,3,5(10)-estratriene-3,17fi-diol.

EXAMPLE 10 Preparation of 3-Alkan0yl Esters A solution of 1 g. of16,16-difluoro-1,3,S(10)-estratriene-3-ol-17-one (the compound ofExample 7) in 10 ml. of pyridine and 2 ml. of acetic anhydride is leftovernight at room temperature. Water is added and the aqueous mixtureextracted with ether. The ether extracts are combined, Washed With 2 Nhydrochloric acid, then water, dried over sodium sulfate, filtered anddistilled in vacuo to give a residue substantially of 16,16-difluor0-1,3,5 10) -estratriene-3-ol-17-one S-acetate.

In a similar manner, 16,16-difluoro-17a-methy1-1,3,5(10)-estratriene-3,17B-diol and16,16-difiuoro-17a-ethinyl-1,3,5(10)-estratriene-3,17B-diol are eachreacted with acetic anhydride in pyridine to give respectively, 16,16-difiuoro 17oz methyl-1,3,5(10)-estratriene-3,17;3-diol 3- acetate and16,l6-difiuoro-17a-ethinyl-1,3,5(10)-estratriene-3,17B-cliol 3-acetate.

By substituting other acid anhydrides such as propionic, valeric andt-butylacetic anhydride for acetic anhydride in the above proceduresthere are obtained the corresponding propionate, valerate andt-butylaceta-te of the aforementioned compounds.

EXAMPLE 11 Preparation of 3-Benz0ic Acid Esters To one gram ofl6,l6-difluoro-1,3,5(10)-estratriene-3- ol-17-one (the compound ofExample 7) in 10 ml. of pyridine is added 2 ml. of benzoyl chloride. Thesolution is left at room temperature for 24 hours, water is added andthe aqueous mixture extracted with ether. The ether extracts arecombined, Washed with 2 N hydrochloric acid, then water, dried oversodium sulfate, filtered and distilled in vacuo to give a residuesubstantially of 16,16-difluoro- 1,3,5 10) -estratriene-3-o1-17-one3-benzoate.

In a similar manner, 16,16-difluoro-17a-mlethy1-L3,5(10)-estratriene-3,17B-diol and16,16-difiuoro-17u-ethinyl-1,3,5(10)-estratriene-3,17fl-diol are eachreacted with benzoyl chloride in pyridine to give respectively, 16,16-difluoro 17,8 methyl 1,3,5(10)-estratriene-3,17 3-diol 3- benzoate and16,16-difluoro-17a-ethinyl-1,3,5(10)-estratriene-3,17/3-diol 3-benzoate.

EXAMPLE 12 16,16-Diflu0r0-1 7oc-M ethyl-1 ,3 ,5 (10 -Estratriene-3,17fl-Dz'ol 3-Benz0ate 17-Acetate One gram of16,16-difiuoro-17a-methyl-1,3,5(10)-estra- 9 triene-3,17,8-diol 3benzoate (prepared as described in Example 11) in 10 ml. of pyridine and2 ml. of acetic anhydride is reacted in the manner described in Example6. The resultant product is isolated as described to give 16,16-difiuoro-17a-methyl-1,3,5 10)-estratriene-3,17fi-diol 3- benzoate17-acetate.

In a similar manner, 16,16-dlfillOI'0-17a-CthlIlY1-L3,5(10)-estratriene-3,17fl-diol 3-benzoate (prepared as described inExample 11) is reacted with pyridine and acetic anhydride to give16,16-difluoro-l7a-ethinyl-l,3,5(10)- estra-triene-3,l7B-diol 3-benzoate17-acetate.

EXAMPLE 13 Preparation of 3,17-Di-L wer Alkanoyl and 3,17-DibenzoateEsters One gram of16,16-difluoro-17amethy1-1,3,5(10)-estratriene-3,17;3-diol (the compoundof Example 8) in ml. of pyridine and 4 ml. of acetic anhydride isreacted in the manner described in Example 6 to give16,16-difiuoro-17amethyl-1,3,5 (10)-estratriene-3,17{3-diol diacetate.

One gram of 16,16-dlflL10'l0-17u-II16LhY1-1,3,5(10)-estratriene-3,17B-diol in 10 ml. of pyridine and 4 ml. of benzoylchloride is reacted in the manner similar to that described in Example 6to give 16,16-difluoro-17a-methy1- 1,3,5 10)-estratriene-3, 17,8-dioldibenzoate.

In a similar manner, 16,16-difluoro-l7a-ethinyl-1,3,5(10)-estratriene-3,17fl-diol (the compound of Example 9) and 16,16difluoro-l,3,5 (10)-estratriene-3,l7{i-diol (prepared as in Example 7)are each reacted with acetic anhydride or benzoyl chloride in pyridineto give the respective di-esters, i.e., l6,16-difluoro-l7a-ethinyl-l,3,5(10)-estratriene-3,17fl-diol diacetate, 16,16-di-fluoro-l, 3,5(10)estratriene-3,17B-diol diacetate, 16,16-difluoro- 17cc ethinyl 1,3,510)-estratriene-3,17fi-diol dibenzoate and 16,16 difiuoro-1,3,5(10)-estratriene-3,17,8-dio1 dibenzoate.

EXAMPLE 14 A solution of 1 g. of 16,16-diflllOIO-17u-1Tl6thYl-1,3, 5(10)-estratriene-3,17;3-diol diacetate (prepared as described in Example13) in 30 ml. of 5% potassium hydroxide in methanol is refluxed forone-half hour. The solution is cooled, diluted with water, thenneutralized with dilute hydrochloric acid. A solid separates which isfiltered, dried and crystallized from acetone-hexane to give 16,16difiuoro 17a-methyl-1,3,5 (10)-estratriene-3, 17fi-diol 17-acetate.

EXAMPLE 15 Alternate Procedure for the Preparation of 3-Meth0xy-16,16-Di-Flu0r0-1,3,5 (10)-Est'ratriene-1 7-One A. 3 methoxy 16 (1hydroxy 1 carbomethoxy)methylene-1,3,5(10)-estratriene-17-one(3-methoxy- 16 ethoxyalyl 1,3,5(10) estratriene 17 one) .To a stirredsolution of 10 g. of sodium methoxide in 60 ml. of ethyl oxalate and 60ml. of benzene under an atmosphere of nitrogen, there is added dropwisea solution containing 10 g. of 3-methoxy-1,3,5(10)-estratriene-17-one in500 ml. of benzene and 100 ml. of tetrahydrofuran. The mixture isstirred under nitrogen at room temperature for 18 hours. The reactionmixture is then poured into 300 m1. of water with stirring andneutralized with 6 N hydrochloric acid. A solid separates which isfiltered, washed with water and dried to give 3-methoxy-16-(1- hydroxy1' carbethoxy)methylene 1,3,5(l0)- estratriene-17-one(3-methoxy-16-ethoxalyl-1,3,5 10)-estratriene-l7-one), which is usedwithout further purification in the following procedure.

B. 3-meth0xy 16,16 difluoro 1,3,5(10) estratriene 17 0ne.3 methoxy 16 (1hydroxy 1' carbethoxy)methylene 1,3,5(10) estratriene 17 one(3-methoxy-16-ethoxalyl-l,3,5 (10)-estratriene-l7-one) is reacted withperchloryl fluoride in t-butanol in the pres- 10 ence of potassiumtbutoxide in the manner of Example 1B. The resultant product is isolatedand purified as described to give3-meth0xy-16,16-difluoro-1,3,5(10)-estratriene-17-one.

EXAMPLE 16 3-Methoxy-16,16-Diflu0r0-17a-(1 -Pr0pynyl) -1,3,5 (10)-Estratriene-I -01 To a stirred solution of 1 g. of3-methoxy-16,16-difiuoro-l,3,5(10)-estratriene-17-one (the compound ofExample 1) in 10 ml. of toluene under an atmosphere of nitrogen is addeda solution of potassium butoxide (prepared from 1 g. of potassium and 14ml. of t-butanol). The solution is cooled to room temperature, stirredfor one hour and then methyl acetylene gas is passed over the solutionfor 8 hours, while maintaining the solution at room temperature. Thereaction mixture is diluted with 2 N hydrochloric acid until stronglyacid, then is extracted with toluene. The toluene extracts are combined,washed with water, dried over sodium sulfate and evaporated in vacuo togive 3-methoxy-l6,l6-difluoro- 17oa-(1-propynyl) 1,3,5 10)-estratriene-l7fi-ol.

EXAMPLE 17 300 mg. of pre-reduced palladized strontium carbonatecatalyst (15%) is added to a solution of 696 mg. of 3- methoxy 16,16di-fluoro 17a ethinyl 1,3,5(10) est-ratriene-17fi-ol (the compound ofExample 3) in 100 m1. of pyridine. The mixture is stirred under anatmosphere of hydrogen until one mole of hydrogen per mole of steroidhas been absorbed. The mixture is then filtered and the filtrate pouredinto 500 ml. of aqueous 10% hydrochloric acid, then the aqueous mixtureextracted with ether. The ethereal extracts are combined, washed with 2N hydrochloric acid, then with water and dried over sodium sulfate. Thedried ethereal solution is evaporated to a residue which is crystallizedfrom acetone-hexane to give 3-methoxy-16,16-difiuoro-17a-viny1- 1,3,5(10) -estratriene-l7fi-ol.

In a similar manner, 3-methoxy-16,16-difluoro-17a-(1-propynyl)-l,3,5(10)-estratriene-17fi-ol (the compound of Example 16)is reduced according to the above-described procedure to give3-methoxy-l6,l6-difluoro-l7a- (l-propenyl)-l,3,5 10)-estratriene-17,8-ol.

EXAMPLE 18 3-Eth0xy-16,16-Diflu0r0-1,3,5 (10) -Estratriene-1 7 -One To 1g. of 16,l6-difiuoro-l,3,5 (10)-estratriene-3-ol-17- one (the compoundof Example 9) in 30 ml. of 10% ethanolic potassium hydroxide solution isadded 3 ml. of diethyl sulfate over a two hour period (0.5 ml. portionsevery 20 minutes). The reaction mixture is stirred for minutes, thendiluted with 150 ml. of water. A solid results which is filtered, washedwith water and dried to give 3-ethoxy-16,16-difiuoro-1,3,5 10-estratriene-17-one.

EXAMPLE 19 3-Methoxy-16J6-Diflu0r0-1,3,5 (10 Estratriene-l 7 3-0l 1 7 -Hemisuccinate and the Sodium Salt T hereof A. 3 methoxy 16,16 difluoro1,3,5(10) estratriene-I7;3-hemisuccinate.To one gram of 3 -methoxy-16,16 difluoro 1,3,5 10) estratriene-17,8-ol (the compound of Example 2)in 10 ml. of pyridine is added one gram of succinic anhydride. Themixture is heated on a steam bath for one hour then cooled and dilutedwith water. A solid separates which is filtered, washed with water anddried to give 3-rnethoxy-16,l6-difluoro-1,3, 5 10)-estratriene-l7fi-ol17-hemisuccinate.

B. 3 methoxy 16,16 diflu ro 1,3,5(10) est ratrien'e-l 7 3-01 17-s0diumhemisuccinater-To 1 g. of3-methoby-16,16-difluoro-1,3,5(10)-estratriene-l7B-ol 17 hemisuccinatesuspended in ml. of water is added 2.04 ml.

11 of a 10% aqueous solution of sodium hydroxide. The resultant aqueoussolution is evaporated in vacuo to a residue of substantially3-methoxy-16,16-difiuor0-1,3, ()-estratriene-17a-ol l7-sodiumhernisuccinate.

EXAMPLE 20 Preparation of Phosphate Esters and the Disodium SaltsThereof A. ]6,16-a'iflaor0-1,3,5(10)-estratriene-3-ol-1 7-0ne 3-phosphate.-A solution of 2 g. of 16,16-difluoro-1,3,5-(l0)-estratriene-3-ol-17-one (the compound of Example 1) in 10 ml. ofpyridine is added to 1.8 g. of phosphorous oxychloride in 10 ml. ofpyridine at 10 C. The reaction mixture is stirred for one hour at 10 C.,then poured slowly with stirring onto crushed ice. The resultant aqueousmixture is made alkaline with a saturated aqueous sodium bicarbonatesolution and washed with ether. The aqueous solution is then acidifiedwith hydrochloric acid. A solid precipitates which is filtered and driedto give 16,l6-difiuoro-1,3,5(10)-estratriene-3-ol- 17-one I i-phosphate.

B. 3-meth0xy-1 6,16-diflu0r0-1,3,5(10)-estratriene-1 7;?- ol17-ph0sphate.A solution of 2 g. of 3-methoxy-16,16-difluoro-1,3,5(10)-estratriene-17fi-ol (the compound of Example 2) inpyridine is reacted with 1.7 g. of phosphorous oxychloride in 10 ml. ofpyridine at --10 C. according to the procedure of Example 20A to give 3-methoxy 16,16 difluoro 1,3,5 (10) estratriene 17B- 01 17-phosphate.

C. The disodiam salt of compounds 20A and 20B. One gram of16,16-difluoro-1,3,5(10)-estratriene-3-ol-l7- one 3-phosphate issuspended in 100 ml. of water and 2.16 ml. of a 10% aqueous solution ofsodium hydroxide is added with stirring. The resultant solution is thenevaporated in vacuo to a residue substantially of 16,16-diiluoro-1,3,5l0)-estratriene-3-ol-17-one 3-disodium phosphate.

Similarily, one gram of 3-methoxy-16,16-difluoro-1,3,5-(10)-estratriene-17fl-ol 17-phosphate is reacted with 10% aqueous sodiumhydroxide to give 3-rnethoxy-16,16-difluoro 1,3,5(10) estratriene 17,601 17 d-isodium phosphate.

EXAMPLE 21 1 6 ,1 6-D ifluoro-l ,3 ,5 (10 -Estratriene-3-Ol-J 7-One3-Suljate and the Potassium Salt Thereof A. 16,16-diflu0r0-1,3,5(10)-estratriene-3-ol-17-one 3- potassium sulfate.A mixture of 10 g. of16,16-difluoro- 1,3,5(10)-estratriene-3-ol-17-one (the compound ofExample 1) and 10 g. of pyridine-sulphur trioxide complex in 100 ml. ofpyridine is stirred for 2 /2 hours at room temperature. The mixture isthen cooled in an ice bath and 10 ml. of aqueous potassium hydroxideadded rapidly with vigorous stirring. The mixture is stirred two minuteslonger, then allowed to cool to room temperature without furtherstirring. The resultant two-phase system is centrifuged at roomtemperature and the pyridine layer decanted. The aqueous residue iswashed with pyridine and the pyridine washes combined with the originalpyridine layer. Ether is then added to the stirred pyridine solutionuntil precipitation is complete. The mixture is then filtered and theresidue dried to give substantially 16,16-d-ifluoro-1,3,5 10)-estratriene-3-ol-17-one 3-potassium sulfate.

B. 16,16-diflu0r0-l,3,5 (10)-estratriene-3-0l-1 7-0ne 3- salfate.--Onegram of 16,l6-difluoro-1,3,5(10)-estratriene-3-ol-17-one 3-potassiumsulfate is dissolved in ml. of water and the solution brought toneutrality by adding hydrochloric acid. A sol-id results which isfiltered and dried to give 16,16-difluoro-1,3,5(10)-estratriene-3-o1-17-one 3-sulfate.

EXAMPLE 22 1 6,]6-Difluor0-1,3,5 (10 -Estratriene-3,1 7,8-Di0l 3-AcetateOne gram of 16,16-difluoro-l,3,5(10)-estratriene-3-ol- 17-one 3-acetate(prepared as described in Example 10) is dissolved in ml. of ethylacetate and 0.25 g. of platinum oxide catalyst added. The mixture isreduced under an atmosphere of hydrogen at room temperature for 24hours. The mixture is then filtered and the filtrate evaporated in vacuoto a residue which is crystallized from aqueous methanol of give16,16-difluoro-1,3,5(10)- estratriene-3,17f3-diol 3-acetate.

Ina similar manner, 16,l6-difluoro-l,3,5(10)estratriene-3-ol-17-one3-benzoate (prepared as described in Example 11) is reduced withhydrogen using platinum oxide catalyst to give16,16-difluoro-1,3,5(10)-estratriene- 3,17fl-diol 3-benzoate.

I claim:

3 methoxy 16 (1' hydroxy 1' carbethoxy)methylene 1,3,5(10) estratriene17 one.

No references cited.

